Objective: To evaluate the effect of phosphodiesterase inhibitors, as potential treatment for Friedreich’s ataxia, in a Drosophila melanogaster model of the disease.

Background: Friedreich’s ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with a prevalence of 2-4/100.000 among European population. It is caused by an abnormally expanded GAA repeat in intron 1 of FXN gene, which results in a deficiency of the encoded frataxin protein. Reduction of frataxin levels lead to Fe accumulation, mitochondrial dysfunction and sensitivity to oxidative stress. Nowadays there is no an effective treatment for FRDA. Recently, we have proposed phosphodiesterase (PDE) inhibitors as potential molecules for pharmacological intervention in the disease (1). To confirm the beneficial effect of PDE inhibitors in a frataxin-depleted condition, we evaluated the use of two PDE inhibitors in a D. melanogaster model of FRDA.

Method: We used a fly model of FRDA developed in our laboratory (2), which shows a decrease of 70% in the mRNA levels of fh (the FXN orthologous in D. melanogaster). The FRDA model flies have a 25% reduction of climbing capabilities comparing with the control flies. Flies were treated with sildenafil (a specific inhibitor of PDE5 that increases the cytosolic levels of cGMP) and rolipram (a PDE4 inhibitor that increases cAMP levels). Each compound was administered in the fly food from larva to adult stage in dose-dependent assays, and its effect was evaluated measuring the motor performance in 7-day-old adults as previously described in Calap-Quintana et al (3). Frataxin levels were measured by RT-qPCR.

Results: We observed that model flies treated with rolipram [10µM] showed a significant improvement in the climbing ability, similar to the untreated control flies. Sildenafil [25µM and 75µM] produced a weak amelioration in the motor phenotype. The frataxin levels were not modified neither with rolipram nor sildenafil treatments.

Conclusion: Rolipram is able to improve the motor performance of the FRDA model flies without increasing the frataxin amount, and probably by modulation the cAMP levels and improving mitochondrial function.

References: (1) Llorens JV, Navarro JA, Martínez-Sebastián MJ, Baylies MK, Schneuwly S, Botella JA, et al. Causative role of oxidative stress in a Drosophila model of Friedreich ataxia. FASEB J. 2007; 21(2): 333-344. (2) Mollá B, Muñoz-Lasso DC, Calap-Quintana P, Fernandez-Vilata A, de la Iglesia-Vaya M, Pallardó FV, et al. Phosphodiesterase inhibitors revert axonal dystrophy in Friedreich’s ataxia mouse model. Neurotherapeutics. 2019. (3) Calap-Quintana P, Soriano S, Llorens JV, Al-Ramahi I, Botas J, Moltó MD, et al. TORC1 inhibition by Rampamycin promotes antioxidant defences in a Drosophila model of Friedreich’s ataxia. PLoS One. 2015; 10(7): e0132376.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/phosphodiesterase-inhibitors-as-a-treatment-for-friedreichs-ataxia/